Method for producing Aspartame derivative, method for purifying the same, crystals thereof and uses of the same

Abstract

N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is prepared by a process comprising: subjecting Aspartame and 3-(3-methoxy-4-hydroxyphenyl)propionaldehyde or derivatives thereof to reductive alkylation in a solvent to produce N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester; and crystallizing said compound.

1. A method for producing
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester, comprising: 
 subjecting N-L-α-aspartyl-L-phenylalanine 1-methyl ester and 3-(3-methoxy-4-hydroxyphenyl)propionaldehyde or a derivatives thereof to reductive alkylation in a solvent to obtain  
 
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester;  
 and (2) crystallizing said  
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester 
 wherein said reductive alkylation comprises catalytic hidrogenation, and  
 wherein said derivative thereof is selected from the group consisting of  
 3-(3-methoxy-4-hydroxyphenyl)-2-propenylaldehyde  
 3-(3-methoxy-4-protected-hydroxyphenyl)propionaldehyde,  
 3-(3-methoxy-4-protected-hydroxyphenyl)-2-propenylaldehyde, and  
 acetals derived therefrom.  
 
 
     
     
       2. The method of  claim 1 , wherein said crystallizing said
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester comprises any one of the following crystallization methods: 
 a. crystallization with a solvent useful for crystallization;  
 b. crystallization after extraction with water; and  
 c. crystallization after separation N-L-α-aspartyl-L-phenylalanine 1-methyl ester.  
 
 
     
     
       3. The method of  claim 1 , wherein said solvent for said reductive alkylation reaction is at least one solvent selected from the group consisting of alcohols, tetrahydrofuran, acetonitrile, toluene, acetic acid and acetic acid esters, and mixed solvent which comprise at least one of these organic solvents and water. 
     
     
       4. The method of  claim 2 , wherein said
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is crystallized by a process of concentration or by a process for solvent substitution.  
 
     
     
       5. The method of  claim 1 , wherein said solvent for said crystallization of said N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester at least one solvent selected from the group consisting of alcohols, tetrahydrofuran, acetonitrile, toluene, ether, acetone, acetic acid, acetic acid esters, and mixed solvent which comprise at least one of these organic solvents and water. 
     
     
       6. The method of  claim 1 , wherein said solvent for said crystallization of said N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is the same solvent which has been used in the reductive alkylation reaction. 
     
     
       7. The method of  claim 4 , wherein said
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is crystallized by solvent substitution using at least one solvent selected from the group consisting of alcohols, tetrahydrofuran, acetonitrile, toluene, ether, acetone, acetic acid, acetic acid esters, and mixed solvents which comprise at least one of these organic solvents and water.  
 
     
     
       8. The method of  claim 1 , wherein said solvent of the said reductive alkylation reaction is one or more alcohols or a mixed solvent of one or more alcohols and water, and the solvent of said crystallization of said
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is one or more alcohols or a mixed solvent comprising one or more alcohols.  
 
     
     
       9. The method of  claim 2 , wherein said
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is crystallization after extraction with water using at least one solvent selected from the group consisting of alcohols, tetrahydrofuran, acetonitrile, toluene, ether, acetone, acetic acid, acetic acid esters, and mixed solvent which comprise at least one of these organic solvents and water.  
 
     
     
       10. The method of  claim 2 , wherein said
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is crystallized after extraction with water and said extraction with water is conducted with a mixed solvent which comprises water and one or more organic solvents, wherein said organic solvent forms a layer which separates from an aqueous layer upon mixture with water, and said  
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is extracted into the aqueous layer.  
 
     
     
       11. The method of  claim 10 , wherein said organic solvent is at least one solvent selected from the group consisting of acetic acid esters, ether, chloroform, dichloromethane, hexane, toluene, alcohols, tetrahydrofuran, acetone, acetonitrile and acetic acid. 
     
     
       12. The method of  claim 2 , wherein said
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is crystalled after having separated N-L-α-aspartyl-L-phenylalanine 1-methyl ester and is crystallized from at least one solvent selected from the group consisting of alcohols, tetrahydrofuran, acetonitrile, toluene, ether, acetone, acetic acid, acetic acid esters, and mixed solvent which comprise at least one of these organic solvents and water.  
 
     
     
       13. The method of  claim 2 , wherein said process for separating N-L-α-aspartyl-L-phenylalanine 1-methyl ester is a process for separating N-L-α-aspartyl-L-phenylalanine 1-methyl ester by crystallization or precipitation with at least one solvent selected from the group consisting of acetic acid esters, ether, chloroform, dichloromethane, hexane, toluene, alcohols, tetrahydrofuran, acetone, acetonitrile, acetic acid and water. 
     
     
       14. The method of  claim 1 , wherein said reductive alkylation reaction is conducted in at least one organic solvent which dissolves the starting materials or a mixed solvent of said organic solvents and water, and when an insoluble material is present in the reaction mixture obtained after said reductive alkylation reaction, said insoluble material is separated by filtration. 
     
     
       15. The method of  claim 1 , wherein said catalytic hydrogenation is conducted in the presence of at least one catalyst selected from the group consisting of palladium, platinum, and rhodium based catalysts. 
     
     
       16. The method of  claim 1 , wherein said catalytic hydrogenation is conducted at a hydrogen pressure of 0.1 to 1 MPa. 
     
     
       17. The method of  claim 1 , wherein said reductive alkylation reaction is conducted at a temperature ranges from 15 to 50° C., and the reaction time of from 2 to 48 hours. 
     
     
       18. The method of  claim 1 , wherein said reductive alkylation reaction is carried out in reaction solvent having a pH of from 4 to 6.5. 
     
     
       19. The method of  claim 1 , wherein the molar ratio of said N-L-α-aspartyl-L-phenylalanine 1-methyl ester to said 3-(3-methoxy-4-hydroxyphenyl)propionaldehyde or derivative thereof ranges from 0.5 to 2. 
     
     
       20. The method of  claim 1 , wherein said 3-(3-methoxy-4-hydroxyphenyl)propionaldehyde or derivative thereof is prepared by subjecting 3-(3-methoxy-4-hydroxyphenyl)-2-propenylaldehyde or acetal thereof, wherein the hydroxyl group may be protected, to reduction to obtain said 3-(3-methoxy-4-hydroxyphenyl)-2-propenylaldehyde or derivative thereof. 
     
     
       21. The method of  claim 20 , wherein said reduction is conducted in the presence of a reduction catalyst or a rhodium based catalyst. 
     
     
       22. The method of  claim 2 , wherein said crystallization of said N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is carried out in the same solvent which has been used in the reductive alkylation reaction. 
     
     
       23. The method of  claim 2 , wherein said solvent of the reductive alkylation reaction is one or more alcohols or a mixed solvent of one or more alcohols and water, and the solvent of the crystallization of said
 N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester is one or more alcohols or a mixed solvent comprising one or more alcohols.